We are investigating the role of eicosanoids in regulating expression of the platelet-derived growth factor receptor (PDGF-R ) in cultured human lung fibroblasts. We have shown that early passage human lung fibroblast isolates constitutively express PDGF-R and avidly proliferate in response to PDGF-AA, which only binds PDGF-R . Importantly, the cyclooxygenase-derived eicosanoid PGE2 markedly attenuates constitutive PDGF-R activity and PDGF-stimulated 3H-thymidine incorporation in the cultured cells. The effects of PGE2 occur at concentrations as low as 50 nM, are dose-dependent, and occur maximally 24 hours following PGE2 addition. Identical results were obtained with several different primary human lung mesenchymal cell lines established in our laboratory from histologically normal lung tissue suggesting that the observed phenomena were not cell line-specific. These findings are particularly important given the known effects of PGE2 on mesenchymal cell proliferation and in light of the recent findings that fibroblasts isolated from patients with idiopathic pulmonary fibrosis have a diminished capacity to synthesize PGE2. Current efforts are focused on delineating the signaling mechanisms whereby PGE2 may modulate PDGF-R expression on lung fibroblasts in vitro. In a related clinical study, we are investigating the role of PDGF receptors in the pathogenesis of fibroproliferative lung disease that develops in patients with cancer receiving high-dose chemotherapy. We are collecting bronchoalveolar lavage fluid and transbronchial biopsy specimens from patients before and after chemotherapy in order to study differences in PDGF receptor expression, regulation and function. Preliminary results suggest that post-chemotherapy BAL fluid stimulates thymidine incorporation in cultured human lung fibroblasts and that this proliferative effect is blocked by inhibitory antibodies to PDGF. This data is consistent with a role of the PDGF/PDGF-receptor pathway in the pathogenesis of the disease. We hope that this clinical study will provide insight into basic cellular, molecular, and biochemical mechanisms responsible for initiating and perpetuating the fibroproliferative response in patients exposed to environmental lung toxins, and will set the stage for a second study aimed at novel therapeutic and preventative strategies for fibroproliferative lung disease.